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Abstract Background Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62LlowCD4+ T cells (effector T cells; %Teff) and CD4+CD25+FOXP3+ T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index. Methods The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer. Results This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation,

Abstract This study quantitatively evaluated the typhoon‐induced sea surface temperature (SST) cooling caused by typhoons Faxai (2019) and Hagibis (2019) using a high‐resolution ocean model and the cooling parameter (Co). Faxai and Hagibis both passed over the ocean south of the eastern part of the Japanese main island, but the associated average SST decreases differed. Faxai produced a decrease of less than 2°C, whereas Hagibis produced a decrease of more than 2°C. The average Co value was 1.6 for Faxai and 3.6 for Hagibis, indicating that SST was more easily cooled by Hagibis than by Faxai, consistent with the observations. The impact of ocean conditions on the typhoon‐induced SST cooling by Hagibis was 2.6 times larger than the impact by Faxai, indicating that the ocean before Hagibis passes is less hard to cool ocean than Faxai. In short, it is important for ocean cooling not only ocean conditions but also typhoon characteristics because in fact, Hagibis cooled the ocean more than Faxai. In addition, the impact of Hagibis's characteristics on the typhoon‐induced SST cooling was 4.8 times larger than the impact of Faxai's characteristics. Thus, SST was more likely to cool by typhoon characteristics in the case of Hagibis. In particular, among Hagibis's characteristics, typhoon size in the horizontal direction had the most efficient effect on SST cooling. Although Co does not consider the effects of the advection of ocean water, we suggest that Co is a practical indicator for estimating SST cooling caused by a typhoon and comparing factors of typhoon‐induced SST cooling in multiple cases.

Abstract This study analyzed the observed data of precipitation and PM2.5 concentration collected over two and a half years at Tsujido, Fujisawa City, to examine a quantitative relationship between the two quantities. It was observed that the PM2.5 concentration decreased as precipitation increased. A composite analysis revealed that the PM2.5 concentration on average decreases by 20.99% 1 h after the onset of precipitation as compared to that 1 h before, which is statistically significant based on a paired t‐test. The PM2.5 concentrations decreased over 8 h period from 5 h (−5 h) before to 3 h (+3 h) after the onset of precipitation, with a particularly dramatic decrease at the onset of precipitation. Analysis of PM2.5 scavenging rates by precipitation intensity showed that the scavenging rate was 2.03% for light precipitation events, 28.15% for moderate precipitation events, and 26.75% for heavy precipitation events, indicating that the scavenging rate increased with moderate precipitation intensity and above. It is suggested that the deposition processes of rainout and washout are effective in reducing PM2.5 concentration with precipitation.

This is a prospective study that has been done to assess the lumbar sagittal alignment of patients positioned prone over an adjustable hinged carbon fiber operating table. The following three variations of table position have been considered: neutral, 20° convex, and 20° concave bending. A total of 33 patients who underwent lumbar disc herniation and lumbar canal stenosis surgery were enrolled. Patients who presented with spinal deformity akin to lumbar scoliosis or spondylolisthesis were excluded. For the surgical procedure, following the induction of endotracheal general anesthesia, patients were positioned prone on the adjustable hinged carbon fiber operating table. Radiographs of the lateral view of the lumbar spine were acquired for the three table positions, i.e., neutral, 20° convex, and 20° concave. The lumbar lordosis was measured on radiographs. The lumbar lordosis presented divergently in all three variations of the table (p < 0.01): 45.2 ± 11.0° in neutral; 52.0 ± 10.7° in 20° lumbar extension bending; and 35.9 ± 10.8° in 20° lumbar flexion bending. The efficacy of table bending was 46.5% in convex and 34.0% in concave bending. In conclusion, the lumbar lordosis in three different table positions were 35.9° in 20° convex bending, 45.2° in neutral, and 52.0° in concave bending. The efficacy of table bending was 46.5% in convex and 34.0% in concave bending.

Abstract The impacts of aerosols on the charge distribution of hydrometeors and lightning flash density in a tropical cyclone (TC) were investigated using a meteorological model coupled with an explicit lightning model. The meteorological model successfully simulated the tripole structure of charge density distribution in a TC, as reported by previous studies. The impacts of aerosols were investigated through a sensitivity experiment with changing the aerosol number concentration. The tripole structure became unclear with increasing aerosol number concentrations. The positive charge distribution located in the lower layer was not seen, and raindrops with negative charge distribution reached the surface. As a result, the vertical structure of the charge density was dipolar in the polluted case. As the tripole structure shifted to dipole, the magnitude of the electric field tended to be large, and the flash number was large. By contrast, in the pristine case, the tripole structure was dominant, and the flash number was much smaller than in the polluted case.

Abstract This article reviews the major outcomes of a 5-year (2011–2016) project using the K computer to perform global numerical atmospheric simulations based on the non-hydrostatic icosahedral atmospheric model (NICAM). The K computer was made available to the public in September 2012 and was used as a primary resource for Japan’s Strategic Programs for Innovative Research (SPIRE), an initiative to investigate five strategic research areas; the NICAM project fell under the research area of climate and weather simulation sciences. Combining NICAM with high-performance computing has created new opportunities in three areas of research: (1) higher resolution global simulations that produce more realistic representations of convective systems, (2) multi-member ensemble simulations that are able to perform extended-range forecasts 10–30 days in advance, and (3) multi-decadal simulations for climatology and variability. Before the K computer era, NICAM was used to demonstrate realistic simulations of intra-seasonal oscillations including the Madden-Julian oscillation (MJO), merely as a case study approach. Thanks to the big leap in computational performance of the K computer, we could greatly increase the number of cases of MJO events for numerical simulations, in addition to integrating time and horizontal resolution. We conclude that the high-resolution global non-hydrostatic model, as used in this five-year project, improves the ability to forecast intra-seasonal oscillations and associated tropical cyclogenesis compared with that of the relatively coarser operational models currently in use. The impacts of the sub-kilometer resolution simulation and the multi-decadal simulations using NICAM are also reviewed.

Transmembrane protein 168 (TMEM168) comprises 697 amino acid residues, including some putative transmembrane domains. It is reported that TMEM168 controls methamphetamine (METH) dependence in the nucleus accumbens (NAc) of mice. Moreover, a strong link between METH dependence-induced adaptive changes in the brain and mood disorders has been evaluated. In the present study, we investigated the effects of accumbal TMEM168 in a battery of behavioral paradigms. The adeno-associated virus (AAV) Tmem168 vector was injected into the NAc of C57BL/6J mice (NAc-TMEM mice). Subsequently, the accumbal TMEM168 mRNA was increased approximately by seven-fold when compared with the NAc-Mock mice (controls). The NAc-TMEM mice reported no change in the locomotor activity, cognitive ability, social interaction, and depression-like behaviors; however, TMEM168 overexpression enhanced anxiety in the elevated-plus maze and light/dark box test. The increased anxiety was reversed by pretreatment with the antianxiety drug diazepam (0.3 mg/kg i.p.). Moreover, the NAc-TMEM mice exhibited decreased prepulse inhibition (PPI) in the startle response test, and the induced schizophrenia-like behavior was reversed by pretreatment with the antipsychotic drug risperidone (0.01 mg/kg i.p.). Furthermore, accumbal TMEM168 overexpression decreased the basal levels of extracellular GABA in the NAc and the high K+ (100 mM)-stimulated GABA elevation; however, the total contents of GABA in the NAc remained unaffected. These results suggest that the TMEM168-regulated GABAergic neuronal system in the NAc might become a novel target while studying the etiology of anxiety and sensorimotor gating deficits.

Shati/Nat8L significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment. We reported that Shati/Nat8L overexpression in mouse NAc attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference. We recently found that Shati/Nat8L overexpression in NAc regulates the dopaminergic neuronal system via the activation of group II mGluRs by elevated N-acetylaspartylglutamate following N-acetylaspartate increase due to the overexpression. These findings suggest that Shati/Nat8L suppresses METH-induced responses. However, the mechanism by which METH increases the Shati/Nat8L mRNA expression in NAc is unclear. To investigate the regulatory mechanism of Shati/Nat8L mRNA expression, we performed a mouse Shati/Nat8L luciferase assay using PC12 cells. Next, we investigated the response of METH to Shati/Nat8L expression and CREB activity using mouse brain slices of NAc, METH administration to mice, and western blotting for CREB activity of specific dopamine receptor signals in vivo and ex vivo. We found that METH activates CREB binding to the Shati/Nat8L promoter to induce the Shati/Nat8L mRNA expression. Furthermore, the dopamine D1 receptor antagonist SCH23390, but not the dopamine D2 receptor antagonist sulpiride, inhibited the upregulation of Shati/Nat8L and CREB activities in the mouse NAc slices. Thus, the administration of the dopamine D1 receptor agonist SKF38393 increased the Shati/Nat8L mRNA expression in mouse NAc. These results showed that the Shati/Nat8L mRNA was increased by METH-induced CREB pathway via dopamine D1 receptor signaling in mouse NAc. These findings may contribute to development of a clinical tool for METH addiction.

Abstract.: A devastating psychiatric disorder, schizophrenia is characterized by three major symptoms, positive and negative symptoms and cognitive deficit. Almost all current therapeutic drugs for schizophrenia have efficacy for positive symptoms, and weak efficacy for negative and cognitive deficit. In particular, social withdrawal, diminished motivation, and anhedonia as the depressive aspects of negative symptoms are resistant to the treatment of antipsychotic drugs. Therefore, there is a need for development of new therapeutic drugs for negative symptoms of schizophrenia, and it is necessary to have comprehensive animal models to understand the neurobiological foundations of their symptoms. In this review, we represent the behavioral phenotypes in available animal models of schizophrenia for drug discovery, focusing on the depressive aspects of negative symptoms. We mention here animal models based on the pathology and epidemiology of schizophrenia, e.g., the pharmacological, neurodevelopmental, genetic, and gene-environment combination models. The animal models of schizophrenia are developed by various approaches and are assessed, but there are few models demonstrating negative symptoms with sensitivities to available therapeutic drugs. The development of comprehensive animal model reflecting negative symptoms and of novel compounds that can remedy them provide certain insight into the neurobiological process of schizophrenia and also point the way to a new therapeutic strategy. Keywords:: schizophrenia, social withdrawal, diminished motivation, anhedonia, animal models

The number of patients with schizophrenia has increased over the past decade. Previously, many studies have been performed to establish its diagnostic criteria, prophylactic methods, and effective therapies. In this study, we analyzed whether the ratios of DNA methylation in CpG islands of the Shati/Nat8l is decreased in model mice of schizophrenia-like phenotype using genomic DNA collected from brain regions and peripheral blood, since the mouse model of schizophrenia-like phenotype, mice treated repeatedly with methamphetamine showed increase of Shati/Nat8l mRNA expression in our previous experiment. The ratios of Shati/Nat8l CpG island methylation were significantly decreased in both the nucleus accumbens and the peripheral blood of model mice compared with those of control mice. We also investigated Shati/Nat8l methylation in the blood of patients with schizophrenia. We found that Shati/Nat8l CpG island methylation ratios were lower in the patients with schizophrenia than in the healthy controls, which is consistent with our findings in the mice model. To our knowledge, this is the first study to show similar alterations in methylation status of a particular genomic DNA site in both the brain and peripheral blood of mice. Furthermore, the same phenomenon was observed in corresponding human genomic sequences of the DNA extracted from the peripheral blood of patients with schizophrenia. Based on our findings, DNA methylation profiles of the CpG island of Shati/Nat8l might be a diagnostic biomarker of schizophrenia.

The single nucleotide polymorphism (SNP) rs13438494 in intron 24 of PCLO was significantly associated with bipolar disorder in a meta-analysis of genome-wide association studies. In this study, we performed functional minigene analysis and bioinformatics prediction of splicing regulatory sequences to characterize the deep intronic SNP rs13438494. We constructed minigenes with A and C alleles containing exon 24, intron 24, and exon 25 of PCLO to assess the genetic effect of rs13438494 on splicing. We found that the C allele of rs13438494 reduces the splicing efficiency of the PCLO minigene. In addition, prediction analysis of enhancer/silencer motifs using the Human Splice Finder web tool indicated that rs13438494 induces the abrogation or creation of such binding sites. Our results indicate that rs13438494 alters splicing efficiency by creating or disrupting a splicing motif, which functions by binding of splicing regulatory proteins, and may ultimately result in bipolar disorder in affected people.